Review Reports - Effectiveness of Topical Cyclosporin-A 0.1% Compared to Combined Topical Cyclosporin-A 0.1% with Topical Sodium Hyaluronate on Interleukin-6 Levels in the Tears of Patients with Dry Eye Disease

Round 1

Reviewer 1 Report

1. Are there any other studies comparing Cyclosporin A application only to Cyclosporin A with other topical artificial tear eye drops? Please include results.

2. Adding side effects of short and long term use of Cyclosporin A would be very helpful.

Author Response

Dear Sir,

According to the associate editor revision for our manuscript entitle “Effectiveness of Topical Cyclosporin-A 0.1% Compared to Combination of Topical Cyclosporin-A 0.1% with Topical Sodium Hyaluronate on Interleukin-6 Levels in the tears of Patients with Dry Eye Disease (vision-2254414)” we will to inform the revision which have been conducted:

REVIEWER 1

Are there any other studies comparing Cyclosporin A application only to Cyclosporin A with other topical artificial tear eye drops? Please include results.

Response:

To clarify, there is no study has compared Topical Cyclosporin-A 0.1% effectiveness compared to the Combination of Topical Cyclosporin-A 0.1% with topical sodium hyaluronate or other artificial tears in the last paragraph of the Introduction section.

“However, until now, no study has compared the effectiveness of topical cyclosporin-A 0.1% to that of topical cyclosporin-A 0.1% combined with topical sodium hyaluronate against more complete clinical parameters in DED patients. More relevant articles included in recent systematic reviews and meta-analyses have only compared the effectiveness of topical cyclosporin-A against or in combination with artificial tears [14].

Adding side effects of short and long term use of Cyclosporin A would be very helpful.

Response:

We have added the side effects of short and long-term use of Cyclosporin A in the last paragraph of the Discussion section.

“In addition, high tolerability is an advantage of the topical administration of cyclosporin-A. The short- and long-term adverse effects of topical cyclosporin-A are relatively mild. The most common is a burning sensation in the cornea when applying the drug to the eye. This is especially true with topical cyclosporin-A, which uses olive or corn oil as a vehicle [50–54].

Reviewer 2 Report

Dry eye disease (DED) is one of the most prevalent ocular diseases that affects visual acuity and quality of life. Pro-inflammatory cytokines such as IL-6 has become a therapeutic target for DED treatment. In this manuscript entitled “Effectiveness of Topical Cyclosporin-A 0.1% Compared to Combination of Topical Cyclosporin-A 0.1% with Topical Sodium Hyaluronate on Interleukin-6 Levels in the tears of Patients with Dry Eye Disease”, the authors used a Randomized Controlled Trial research design to determine the effectiveness of monotherapy compared to combination therapy in improving clinical symptoms and reducing IL-6 levels in the tears of DED patients.

Overall this is a highly clinically relevant piece of work. The analysis is nicely performed and the conclusions are reasonable, but a few issues listed below need to be addressed.

1. In this manuscript, the authors elaborated on mechanisms of sodium hyaluronate in repairing DED. It is as important to discuss Cyclosporin-A mechanism of action in immunomodulation and DED treatment.

2. Previous randomized studies on the efficacy and safety of Ikervis in treatment of DED are worth citing (Baudouin et al., 2017; Leonardi et al., 2016).

3. What are the units for IL-6 levels in Fig 3/Table 4?

4. Please clarify why TBUT score differs significantly between two groups prior to treatments (Table 5).

5. Due to the lipophilic nature of cyclosporine A, it should also be noted that the bioavailability of Cyclosporine A could be affected by its formulation (for example, lipid-based emulsion vs aqueous solution). This could account for the discrepancies of clinical outcomes of Cyclosporine A on DED patients among different studies.

6. There are pro-inflammatory cytokines other than IL-6 (ie IL-8, TNF-α) that are more significantly correlated with DED clinical parameters. I am curious how are those cytokines changed in patients after treatment.

7. Sodium hyaluronate eye drops can be acquired easily over the counter while Ikervis is by prescription only. Considering the cost efficiency, along with the potential adverse effect of Cyclosporin-A, the superiority of the combination therapy is more convincing only if it demonstrates significantly greater improvements over the Sodium hyaluronate eyedrops alone in future studies.

Typos:

L87, L93: “OSDI ³13”, “3” should be “>”

L97: “Whartman” should be “Whatman”

Author Response

Dear Sir,

We look forward to hearing from you

Best Regards,

Author

Author Response File: Author Response.pdf

Reviewer 3 Report

This study evaluated the effectiveness of topical administration of Cyclosporine A monotherapy and Cyclosporine A with Hyaluronic acid combination therapy in managing Dry Eye Syndrome (DED) in humans. The evaluation included standard clinical measures and IL-6 levels determination in human tears. IL-6 is increasingly recognized as a therapeutic target in recent DED research, and exploring the relationship between IL-6 levels in human tears and other tests is crucial. The study's main contribution is shedding light on the potential benefits of combining Hyaluronic acid with Cyclosporine A in managing DED and further elucidating the role of IL-6 as a biomarker for DED severity. Overall, this research provides valuable insights into the effective management of DED in humans and could potentially guide the development of more targeted therapies for this condition.

1. In the introduction part, it would be helpful if the author could further explain the significance of IL-6 as an observation index in DED. This could include a brief overview of the role of IL-6 in DED pathogenesis and previous studies that have utilized IL-6 as a marker for DED severity. This addition would strengthen the significance and novelty of your research and provide a more explicit rationale for your choice of IL-6 as the main observation index.

2. As the author mentioned, previous studies have reported the beneficial effects of Hyaluronic acid (HA) in improving DED symptoms, particularly in the form of artificial tears (PMID: 35514082). In this regard, it would be helpful if the author could elaborate on the relationship between HA-based eye drops and IL-6 levels in DED.

3. Regarding your manuscript's discussion section, it might be beneficial to consider including the findings from the randomized multicenter evaluation mentioned in the following article: DOI: 10.1038/s41598-022-21330-0. Additionally, discussing the similarities and differences between your results and those reported in this study could further strengthen the conclusions drawn from your research.

4. Please add the corresponding unit in Table 4, Table 6, and Figure 3. It will be easier to understand.

Author Response

Dear Sir,

REVIEWER 3

In the introduction part, it would be helpful if the author could further explain the significance of IL-6 as an observation index in DED. This could include a brief overview of the role of IL-6 in DED pathogenesis and previous studies that have utilized IL-6 as a marker for DED severity. This addition would strengthen the significance and novelty of your research and provide a more explicit rationale for your choice of IL-6 as the main observation index.

Response:

We have explained the significance of IL-6 as an observation index in DED in the second paragraph of the introduction section.

“The cytokine IL-6 plays an immunostimulatory role in which it can increase Th17 cell activation, leading to an escalating inflammatory response on the ocular surface [5]. Unlike other…..”

As the author mentioned, previous studies have reported the beneficial effects of Hyaluronic acid (HA) in improving DED symptoms, particularly in the form of artificial tears (PMID: 35514082; author Hynnekleiv L). In this regard, it would be helpful if the author could elaborate on the relationship between HA-based eye drops and IL-6 levels in DED.

Response:

We have elaborate on the relationship between HA-based eye drops and IL-6 levels in DED in the fifth paragraph of the discussion section.

“Regarding the IL-6 tear levels, sodium hyaluronate may hinder the abundant secretion to the ocular surface …”

Regarding your manuscript's discussion section, it might be beneficial to consider including the findings from the randomized multicenter evaluation mentioned in the following article: DOI: 10.1038/s41598-022-21330-0 (author Lee, J.E, title A randomized multicenter evaluation of the efficacy of 0.15% hyaluronic acid versus 0.05% cyclosporine A in dry eye syndrome). Additionally, discussing the similarities and differences between your results and those reported in this study could further strengthen the conclusions drawn from your research.

Response:

We have included the findings from the randomized multicenter evaluation from Lee et al. (2022) as the reviewer’s suggestion. In addition, we have discussed the similarities and differences between our results and those reported in the third paragraph of the discussion section.

“However, a recent multicenter study showed that 0.15% sodium hyaluronate was equivalently effective and safer than …”

Please add the corresponding unit in Table 4, Table 6, and Figure 3. It will be easier to understand.

Response:

We have revised the table 4, 6 and figure 3.

We look forward to hearing from you

Best Regards,

Author

Reviewer 4 Report

Priani et al. provide evidence in this article that combination of cyclosporin with sodium hyaluronidase is a better treatment option over single use of cyclosporin. However, the way data is presented is confusing to understand. My suggestions are:

1. make all the table clear and p value is given for the same table using wilcoxon or paired-t test and also write why you used different statistics.

2. What is unit of IL-6 concentration.

3. plot IL-6 graph in different treatment group that will make sense how it changes compared to control (Figure 3).

4. In table 6, combined treatment increases IL-6 level or no change? this need clarification.

Author Response

Dear Sir,

REVIEWER 4

Make all the table clear and p value is given for the same table using wilcoxon or paired-t test and also write why you used different statistics.

Response:

We have revise accordingly.

What is unit of IL-6 concentration.

Response:

We have revise accordingly (pg/mL)

Plot IL-6 graph in different treatment group that will make sense how it changes compared to control (Figure 3).

Response:

We have revised the graph in Figure 3 to compare IL-6 levels between treatment periods according to dry eye severity (TBUT values). We did not make a plot IL-6 graph in the different treatment groups (Group A vs. Group B) to avoid replication data shown in Table 3.

In table 6, combined treatment increases IL-6 level or no change? this need clarification.

Response:

In Table 6, the data showed the combination of IL-6 levels before and after treatment to describe the contribution of IL-6 to the severity of DED (based on TBUT levels) in the entire research period, both before and after treatment. The change of IL-6 levels in combined treatment (Group B) is described in Table 4. There were significant decreases in IL-6 levels after receiving the combined treatment.

We look forward to hearing from you

Best Regards,

Author

Round 2

Reviewer 4 Report

The figures are not clear and easy to understand. The revised version is convincing